Heritability of Subcortical Volumetric Traits in Mesial Temporal Lobe Epilepsy

Saud Alhusaini,Mary Fitzsimons,Parameswaran M Iyer,James F Meaney,Andrew J Fagan,Norman Delanty,Elijah Chaila,Cathy Scanlon,Gianpiero L Cavalleri,Gerard Boyle,Sinead Maguire,Paul Brennan,Lisa Ronan,Gabor Borgulya,Daniel Costello,Colin P Doherty,Xi-Nian Zuo

doi:10.1371/journal.pone.0061880

Abstract

ObjectivesWe aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE.MethodsMRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated ‘sporadic’ MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity.ResultsMTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population.ConclusionsThe findings indicate that volume deficits for many subcortical structures in ‘sporadic’ MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE.

Highlights

Temporal lobe epilepsy (TLE), the most prevalent form of partial epilepsy in adults, has long been considered an acquired condition
Significant bilateral volume deficits were observed in the putamen in both left and right mesial TLE (MTLE) patients [70 with hippocampal sclerosis (MTLE+hippocampal sclerosis (HS)) patient groups
The results indicate that subcortical volume deficits are significant in MTLE+HS but apparently absent from MRInegative TLE patients

Summary

Introduction

Temporal lobe epilepsy (TLE), the most prevalent form of partial epilepsy in adults, has long been considered an acquired condition. In non-familial (sporadic) forms of TLE, the underlying genetic architecture appears complex and a number of susceptibility genes are believed to interact with several environmental factors to produce the disease phenotype [4]. TLE can be classified into mesial and lateral subtypes. The pathologic hallmark of the more common mesial TLE (MTLE) is hippocampal sclerosis (HS), which is identified in approximately 65–70% of patients [5]. In the remaining 25–30% of MTLE patients, despite having similar seizure semiology to MTLE+HS, no evidence of hippocampal abnormalities can be identified by MRI. This group of patients is often referred to as MRI-negative TLE

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